This invention relates to substituted achiral 2H-pyran-2,6-(3H)-dione derivatives which are useful for inhibiting the symptoms of an allergic response resulting for an antigen-antibody reaction. More specifically, the compounds of this invention are surprisingly effective in inhibiting the release and/or formation and release of pharmacologically active mediators such as histamine, serotonin and slow-reacting substance of anaphylaxis (SRS-A) from effector cells which are produced and/or released as a result of an interaction of antigen and specific antibody fixed to the cell surface (allergic reaction). These properties enable the subject compounds to be useful in various allergic diseases such as allergic ocular diseases, asthma, rhinitis and urticaria.
The compounds of this invention are represented by the following general structural formula: ##STR2## or a pharmaceutically acceptable salt thereof, where R is --(CH.sub.2).sub.m OH or --CH((CH.sub.2).sub.n CH.sub.2 OH).sub.2 where m is 1-5 and n is 1-4.
These compounds are conveniently prepared, as a last step reaction, as follows. ##STR3## Thus, the 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and the appropriately substituted aniline are heated at reflux in an appropriate organic solvent, an alcohol such as methanol for example, for one to three hours to give the product.
Mono- and di-alkyl metal salts, such as the mono- and di-sodium or potassium salts are readily obtained by treatment with the appropriate alkali metal alkoxide, for example methoxide, in an alkanol solvent such as methanol. They can also be prepared by treatment with aqueous alkali metal hydroxides in water.
The pyran-2-one starting material is obtained by reaction of acetonedicarboxylic acid with acetic anhydride in sulfuric acid at elevated temperature. The reaction product actually has several tautomeric structures as shown in U.S. Pat. No. 4,165,365 but for convenience it is designated here as 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one. Due to the tautomeric forms of the pyran-2-one starting material, these compounds will have the following tautomeric structures: ##STR4## where Ar is an aniline fragment of the same structure as represented by formula I. Convenience dictates use of one tautomeric form. The enamine pyran-2,6-dione form has been chosen to represent all tautomeric forms here. It is fully intended that all tautomeric forms are covered by this invention. The use of this single tautomer to represent the invention is not limiting of the invention.
The substituted aniline starting materials used herein are conveniently prepared by established preparative methods.
Wiley, R. H., et. al., J. Org. Chem., 21, 686-688 (1956) has reported the reaction of amines with reaction product of acetonedicarboxylic acid and acetic anhydride, the latter designated 5-carboxydehydroacetic acid. Similarly, Kiang, A. K. et. al. J. Chem. Soc., 2721-6, (1971) has disclosed such reaction products with amines. However, there is no disclosure of products represented by formula I. See also U.S. Pat. No. 4,165,365, issued Aug. 21, 1979 for a similar method for preparing substituted anilines.
The substituted aniline structures of this invention were prepared by the following schematics. The symbol R refers to a protecting group in each of these schemes. Compounds where R is --CH.sub.2 OH are prepared as follows: ##STR5##
Compounds where R is --CH(CH.sub.2 OH).sub.2, are prepared as illustrated in Reaction Scheme II. ##STR6##
In the two preceding reaction schemes, the tert-butyl ethers illustrate the generic use of a group to protect the alcohol function. Other protecting groups may be used in place of the tert-butyl group, so long as they effectively protect the particular alcohol.
The hydroxy acids needed to make substituted anilines where R equals --(CH.sub.2).sub.m OH and m is 2-5 are prepared as illustrated in reaction Scheme III. These acids are then used in place of formula 4 in Reaction Scheme I to form substituted anilines which are used to make compounds of formula I as illustrated in the remaining steps of Reaction Scheme I. ##STR7##
Where m is 2, the ester of acetic acid is deprotonated with a strong base and alkylated with ethylene oxide to obtain the 3-hydroxypropionate (M. Rathke et. al., J. Am. Chem. Soc., 1971, 93, 2319). Herein, it is preferred to use the tert-butyl acetate and lithium diisopropylamide (LDA) as the base in the presence of ethylene oxide to yield tert-butyl-3-hydroxypropionate.
The free hydroxyl group can be protected by conversion to an ether, preferably the tert-butyl ether effected by treating the 3-hydroxypropionate with isobutylene in the presence of an acid such as sulfuric acid.
The free acid can be prepared by basic hydrolysis, preferably in the presence of sodium carborate in water and methanol. This acid (3-tert-butoxypropionic acid) can be converted to the substituted aniline (m=2) as illustrated in Examples 3, 4 and 5.
For m is 3, gamma-butyrolactone can be converted to 4-tert-butoxybutyric acid by ring opening in the presence of an alkanol such as methanol and a catalytic amount of a mineral acid such as sulfuric acid (S. Patai, "The Chemistry of Carboxylic Acids and Esters", pp. 103-136; Interscience Publishers, New York, 1969); protection of the free hydroxyl as an ether, preferably as the tert-butyl ether; and basic hydrolysis using the conditions described above. This protected 4-hydroxybutyric acid can be converted to the substituted aniline (m=3) as illustrated in Examples 3, 4 and 5.
Where m is 4, delta-valerolactone can be converted to protected 5-hydroxypentanoic acid (example: 5-tert-butoxypentanoic acid) as described for 4-hydroxybutyric acid in the preceding paragraph. This acid can be converted to the substituted aniline (m=4) as illustrated in Examples 3, 4 and 5.
2-Oxepanone can be converted to a protected 6-hydroxyhexanoic acid as described for the 4-hydroxybutyric acid. These acids can be converted to the substituted aniline (m=5) as illustrated in Examples 3, 4 and 5.
Substituted anilines where R is --CH((CH.sub.2)nOH).sub.2 and n is 2-4 are prepared as illustrated in Reaction Scheme IV. ##STR8##
Thus, for n equals 2, a protected 3-hydroxypropionic acid (eg., 3-tert-butoxypropionic acid) can be deprotonated with a strong base such as LDA and alkylated with ethylene oxide. This intermediate alcohol can be protected as an ether, preferably as the tert-butyl ether in the presence of isobutylene and sulfuric acid to yield a compound illustrated by 2-(2-tert-butoxyethyl)-4-tert-butyoxybuturic acid. This acid can be converted to the aniline (n=2) as illustrated in Examples 3, 4 and 5.
For n equals 3, 4-alkoxybutyric acid can be deprotonated with a strong base such as LDA and alkylated with 1-bromo-3-(tert-butoxy)propane (prepared by protection of 3-bromopropanol). This yields 53(3-tert-butoxypropyl)-5-tert-butoxypentanoic acid which can be converted to the aniline (n=3) as illustrated in examples 3, 4 and 5.
Where n is 4, 5-alkoxypentanoic acid, or a similarly protected 5-hydroxypentanoic acid, can be deprotonated with a strong base such as LDA and alkylated with 1-bromo-4-tert-butoxybutane (prepared from 3-butene-1-01 by bromination to the terminus of the double bond and protection of the hydroxyl group). This yields a 2-(4-tert-butoxybutyl)-6-tert-butoxyhexanoic acid, or similarly protected compound, which can be converted to the aniline (n=4) as illustrated in Examples 3, 4 and 5.
The preferred compounds are those where R is --(CH.sub.2).sub.m OH and --CH((CH.sub.2).sub.n CH.sub.2 OH).sub.2 and where m is 1-5 and 0-4. Most preferred are:
5-acetyl-4-hydroxy-3-[1-[[3,5-bis-N-(2-hydroxymethyl-3-hydroxy-propionamido )phenyl]amino]ethylidene]-2H-pyran-2,6-(3H)-dione; and
5-acetyl-4-hydroxy-3-[1-[[3,5-bis-N-(2-hydroxymethyl-3-hydroxy-propionamido )phenyl]amino]ethylidene]-2H-pyran-2,6-(3H)-dione.
Included in this invention is the method of inhibiting the symptoms of an allergic response resulting from an antigen-antibody reaction which comprises administering to an animal a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of a pharmaceutical composition. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually the method of this invention will be practiced when relief of allergic symptoms is specifically required, however, the method is also usefully carried out as continuous or prophylactic treatment. A particular application is the treatment of various ocular allergies such as vernal keratoconjunctivitis, allergic conjunctivitis, chronic conjunctivitis and giant papillary conjunctivitis by topical administration of these compounds to the eye in a suitable ophthalmic vehicle. Another application is a method of relieving or preventing allergic airway obstruction which comprises administering to an animal a therapeutically effective amount at suitable intervals. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the allergic condition being treated, and so forth.
The compounds of this invention may be administered in conventional pharmaceutical compositions comprising an appropriate amount of a compound of formula I in association with a pharmaceutical carrier of diluent. The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, i.e., topically, orally, parenterally or by inhalation. Usually a compound is administered to a mammal in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response. Whem employed in this manner, the dosage of the composition is such that from 0.5 mg. to 500 mg. of active ingredient are administered at each application. For convenience, equal doses will be administered 1 to 4 times daily with the daily dosage regimen being about 0.5 mg. to about 2000 mg.
For the prophylactic treatment of ocular allergies, the compositions will be in a form suitable for administration by topical application to the eye. Thus, the compositions will comprise a solution or suspension of the active ingredient in a water-based formulation for administration as eye drops, a spray or a suitable solid form for ophthalmic use. For the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus, the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively, the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant such as dichlorodifluoromethane or chlorotrifluoroethane to be administered from a pressurized container. The compositions may also comprise the solid active ingredient diluted with a solid diluent, e.g., lactose, for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid, it may be present in less, equal or greater amounts than the solid active ingredient.
A wide variety of other pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge for oral administration. The amount of solid carrier will vary widely but preferably will be about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule, or an aqueous or non-aqueous liquid suspension.
Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.